Method for treating substance abuse withdrawal

ABSTRACT

This invention provides a method for treating a condition resulting from the cessation or withdrawal of tobacco or nicotine, opioids, ethanol or combinations thereof comprising administering an effective amount of 4-chloro-5-(imidazoline-2-y(amino)-6-methoxy-2-methylpyrimidine.

This application is a division of application Ser. No. 08/695,451, filedon Aug. 12, 1996, now U.S. Pat. No. 5,732,717, which claims the benefitof U.S. Provision Application No. 60-002,341, filed Aug. 15, 1995 nowabandoned.

FIELD OF THE INVENTION

The present invention is in the fields of pharmacology andpharmaceutical chemistry and provides a method for using4-chloro-5-(imidazoline-2-ylamino)-6-methoxy-2-methylpyrimidine, for thetreatment of smoking cessation, nicotine withdrawal, opioid withdrawal,ethanol withdrawal, and combinations thereof, and alleviation of thecraving for a tobacco product, nicotine, opioids, ethanol andcombinations thereof.

BACKGROUND OF THE INVENTION

It is well known that the chronic administration of nicotine, opioids,ethanol or combinations thereof results in tolerance and, eventually,dependence. The use of tobacco, opioids, and ethanol are extremelywidespread in many countries, despite the well known adverse effects oftheir use.

Many people who regularly use tobacco products would like to quit butcannot because they are addicted to the psychoactive drug that is thedependence-producing constituent of tobacco, nicotine, Benowitz, N. Eng.J. Med., 319:20, 1318-1330 (1988).

Benowitz notes that nicotine may also contribute to various diseases,including cancer, heart disease, respiratory disease and otherconditions, for which tobacco use is a risk factor, particularly heartdisease. Nicotine is present in cigarettes and other tobacco productsthat are smoked or chewed. These tobacco products are addictive andassociated with heart and lung diseases, and other serious diseasestates.

Vigorous campaigns against the use of tobacco have taken place, and itis now common knowledge that the cessation of tobacco use brings with itnumerous unpleasant withdrawal symptoms, which include irritability,anxiety, restlessness, lack of concentration, lightheadedness, insomnia,tremor, increased hunger and weight gain, and, of course, an intensecraving for tobacco.

A few pharmaceutical agents have been reported as useful to treatnicotine dependence, including clonidine, an α₂ -adrenergic agonist, andalprazolam, a benzodiazepine agonist. Receptor antagonists such asmecamylamine have also been used. A few of the benzodiazepinepsychotropic drugs have been described as of some use in tobaccocessation but are not in widespread use. Some serotonin affecting drugshave been described as anti-smoking aids, particularly includingbuspirone, which has been described by West et al. as a promising aid topeople trying to cease the use of tobacco, Psychopharmacology 104:91-96(1991).

Benowitz reports that the most effective treatment thus far has beennicotine substitution therapy, using nicotine gum, or nicotine-providingtransdermal patches to slowly wean individuals from their addiction tonicotine and their use of tobacco products containing nicotine.Unfortunately, the nicotine substitution therapy involves theadministration of the psychoactive constituent of tobacco. Nicotinesubstitution must be tapered, frequently leading to nicotine withdrawaland subsequent relapse to use of tobacco products. Nicotine replacementis generally accepted as most effective when combined withhabit-modifying psychological treatment and training. There is a needfor a therapy having a desirable side effect profile, to relievenicotine withdrawal symptoms, including the long term cravings fornicotine.

The opioids are well known psychoactive drugs that, with use, inducetolerance and dependence upon the psychoactive drug being administered.Drug abuse and dependence, particularly of opioids, are viewed withconcern by the world community. Withdrawal symptoms from the cessationof opioid use vary greatly in intensity depending on numerous factorsincluding the dose of the opioid used, the degree to which the opioideffects on the CNS are continuously exerted, the duration of chronicuse, and the rate at which the opioid is removed from the receptors.These withdrawal symptoms include craving, anxiety, dysphoria, yawning,perspiration, lacrimation, rhinorrhoea, restless and broken sleep,irritability, dilated pupils, aching of bones, back and muscles,piloerection, hot and cold flashes, nausea, vomiting, diarrhea, weightloss, fever, increased blood pressure, pulse and respiratory rate,twitching of muscles and kicking movements of the lower extremities.

Although oral opioids are relatively nontoxic, chronic use is associatedwith minor endocrine abnormalities, constipation and some sleepdisturbance. Nevertheless, the life expectancy of opioid addicts ismarkedly reduced, due to overdose, drug-related infections, suicide andhomicide.

Medical complications associated with injection of opioids include avariety of pathological changes in the CNS including degenerativechanges in globus pallidus, necrosis of spinal gray matter, transversemyelitis, amblyopia, plexitis, peripheral neuropathy, Parkinsoniansyndromes, intellectual impairment, personality changes, andpathological changes in muscles and peripheral nerves. Infections ofskin and systemic organs are also quite common including staphylococcalpneumonitis, tuberculosis, endocarditis, septicemia, viral hepatitis,human immunodeficiency virus (HIV), malaria, tetanus and osteomyelitis.

Pharmaceutical agents used in treating opioid dependence includemethadone, which is an opioid, and opioid antagonists, primarilynaloxone and naltrexone. Clonidine has been shown to suppress someelements of opioid withdrawal but suffers from the side effects ofhypotension and sedation, which can be quite extreme. Habit-modifyingpsychological treatment and training are frequently adjunctive therapyused in association with pharmaceutical agents. There is a need for atherapy having a more desirable side effect profile, to relieve opioidwithdrawal symptoms.

Ethanol is probably the most frequently used depressant in most culturesand a major cause of morbidity and mortality. Repeated intake of largeamounts of ethanol can affect nearly every organ system in the body,particularly the gastrointestinal tract, cardiovascular system, and thecentral and peripheral nervous systems. Gastrointestinal effects includegastritis, stomach ulcers, duodenal ulcers, liver cirrhosis, andpancreatitis. Further, there is an increased rate of cancer of theesophagus, stomach and other parts of the gastrointestinal tract.Cardiovascular effects include hypertension, cardiomyopathy and othermyopathies, significantly elevated levels of triglycerides andlow-density lipoprotein cholesterol. These cardiovascular effectscontribute to a marked increase risk of heart disease. Peripheralneuropathy may be present as evidenced by muscular weakness,parathesias, and decreased peripheral sensation. Central nervous systemeffects include cognitive deficits, severe memory impairmentdegenerative changes in the cerebellum, and ethanol-induced persistingamnesiac disorder in which the ability to encode new memory is severelyimpaired. Generally, these effects are related to vitamin deficiencies,particularly the B vitamins.

Individuals with ethanol dependence exhibit symptoms and physicalchanges including dyspepsia, nausea, bloating, esophageal varices,hemorrhoids, tremor, unsteady gait, insomnia, erectile dysfunction,decreased testicular size, feminizing effects associated with reducedtestosterone levels, spontaneous abortion, and fetal alcohol syndrome.Symptoms associated with ethanol cessation or withdrawal include nausea,vomiting, gastritis, hematemises, dry mouth, puffy blotchy complexion,and peripheral edema.

The generally accepted treatment of ethanol withdrawal symptoms andconditions is accomplished by administering a mild tranquilizer such aschloridiazepoxide. Typically, vitamins, particularly the B vitamins, arealso administered. Optionally, magnesium sulfate and/or glucose are alsoadministered. Nausea, vomiting and diarrhea are treated symptomaticallyat the discretion of the attending physician. Disulfiram may also beadministered for help in maintaining abstinence. If ethanol is consumedwhile on disulfiram, acetaldehyde accumulates producing nausea andhypotension. There is a need for a therapy, effective in relievingsymptoms and conditions resulting from ethanol withdrawal having a moredesirable side effect profile.

There is a definite need in substance abuse withdrawal therapy for apharmaceutical agent to relieve withdrawal symptoms and conditions thatis not itself an addictive agent, as with nicotine and methadone; areceptor antagonist, such as naloxone and naltrexone, that induces orexacerbates withdrawal symptoms and conditions; or an enzyme inhibitorthat induces or exacerbates withdrawal symptoms and conditions; and hasan acceptable side effect profile.

Surprisingly, applicants have discovered that4-chloro-5-(imidazoline-2-ylamino)-6-methoxy-2-methylpyrimidine can beuseful for treating symptoms and conditions produced by cessation orwithdrawal from the use of nicotine and tobacco products, opioids, orethanol and combinations thereof.

SUMMARY OF THE INVENTION

The presently claimed invention provides a method for inhibiting one ormore symptoms or a condition resulting from cessation or withdrawal fromthe use of tobacco, nicotine, opioids, ethanol or combinations thereofcomprising administering an effective amount of4-chloro-5-(imidazoline-2-ylamino)-6-methoxy-2-methylpyrimidine or apharmaceutically acceptable salt thereof to a mammal in need of suchtreatment.

The invention also provides a method of assisting a mammal who usestobacco, nicotine, opioids, ethanol or combinations thereof to cease orreduce such use, as well as a method of preventing a mammal who hasceased or reduced the use of tobacco, nicotine, opioids, ethanol orcombinations thereof from resuming such use, comprising administering tosuch mammal an effective amount of4-chloro-5-(imidazoline-2-ylamino)-6-methoxy-2-methylpyrimidine or apharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

Substance (nicotine, opioid and ethanol) dependence is a cluster ofcognitive, behavioral and physiological symptoms demonstrating there isa continuing use of the substance despite significant substance-relatedproblems. There is a pattern of repeated self-administration thatresults in tolerance, withdrawal and compulsive substance-takingbehavior.

Tolerance is the need for significantly increased amounts of thesubstance to achieve the desired effect, or a markedly diminished effectwith continued use of the same amount of the substance.

Generally, withdrawal is a behavioral change, having physiological andcognitive components, that occurs when blood or tissue concentrations ofa substance decline in an individual who had maintained prolonged heavyuse of the substance. After developing withdrawal symptoms, anindividual is likely to take the substance to relieve or avoid thosesymptoms.

The compound4-chloro-5-(imidazoline-2-ylamino)-6-methoxy-2-methylpyrimidine(moxonidine) is known and described in U.S. Pat. No. 4,323,570 which isincorporated herein by reference in its entirety.

As used herein, the term "mammal" means the Mammalia class of highervertebrates. The term "mammal" includes, but is not limited to, a human.The term "treating" as used herein includes therapeutic and prophylaxisof the symptoms and named condition and amelioration or elimination ofthe conditions once it has been established.

As used herein, the term "opioid" means any natural opioid (opiate),semisynthetic and synthetic exogenous substance that binds to one ormore opioid receptor subtype and produces agonist action. The threeknown opioid receptor subtypes include mu, kappa and delta. Examples ofopioids include opium, morphine, heroin, codeine, pentazocine,buprenorphine, meperidine, butorphanol, feutanyl, nalbuphine,hydromorphone, oxycodone, oxymorphone and methadone.

As used herein, the term "withdrawal" or "cessation and withdrawal"shall refer to symptoms and conditions resulting from: diminished ordiscontinued administration and use of tobacco products, diminished anddiscontinued administration and use of nicotine, diminished ordiscontinued administration and use, injection or orally, of one or moreopioid, diminished or discontinued administration and use of ethanol,and any combination of two or more thereof. Such nicotine, opioid, andethanol withdrawal symptoms and conditions are characterized in theDSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th Ed.(1994). The DSM-IV was prepared by the Task Force on Nomenclature andStatistics of the American Psychiatric Association, and provides cleardescriptions of diagnostic categories. The skilled artisan willrecognize that there are alternative nomenclatures, nosologies, andclassification systems for pathologic psychological conditions and thatthese systems evolve with medical scientific progress.

The criteria for substance dependence set forth in DSM-IV is a patternof substance use, leading to clinically significant impairment ordistress as manifested by at least three selected from the followinggroup, occurring at any time within the same twelve month period: (1)tolerance as defined by either (a) a need for substantially increasedamounts of the substance to achieve the desired effect; or (b)substantially diminished effect with continued use of the same amount ofthe substance; (2) withdrawal, as demonstrated by either (a) thecharacteristic withdrawal syndrome for the specific substance; or (b)the same, or a closely related substance is taken to relieve or avoidwithdrawal symptoms; (3) the substance is often taken in larger amountsor over a longer period then was intended; (4) there is a persistentdesire or unsuccessful efforts to cut down or control substance use; (5)a great deal of time is spent in activities to obtain the substance, usethe substance, or recover from its effects; (6) important social,occupational or recreational activities are given up or reduced becauseof substance use; and (7) the substance use is continued despiteknowledge of having a persistent or recurrent physical or psychologicalproblem that is likely to have been caused or exacerbated by thesubstance.

Substance dependence can be with physiological dependence; that isevidence of tolerance or withdrawal is present, or without physiologicaldependence, where no evidence of tolerance or withdrawal is present.

Four of the conditions include remission. These types of remission arebased on the interval of time that has elapsed since the cessation ofdependencies and whether there is continued presence of one or more ofthe symptoms included in the criteria for dependencies.

The qualifier "early full remission" is used when for at least onemonth, but for less than twelve months, no symptom of dependence hasbeen met.

The qualifier "early partial remission" is used when for at least onemonth but less than 12 months, one or more symptoms for dependence hasbeen met, but the full criteria for dependence has not been met.

The term "sustained full remission" is used when none of the symptoms ofdependence have been met at any time during a period of twelve months orlonger.

The term "sustained partial remission" is used if the symptoms fordependence have not been met for a period of twelve months or longer,however, one or more symptom for dependence has been met.

The qualifier "on agonist therapy" is used if the subject is on aprescribed agonist medication and no symptom for dependence has been metfor that class of medication for at least the past month. It alsoapplies to those being treated for dependence using a partial agonist.

The term "in a controlled environment" is used if the subject is in anenvironment where access to substances of abuse are restricted and nosymptom for dependence has been met for at least the past month.

With substance withdrawal, the essential feature is the development of asubstance-specific behavioral change, with physiology and cognitiveconcomitants, that is due to the cessation of, or reduction in, heavyand prolonged substance use. The substance-specific symptoms causeclinically significant distress or impairment in social, occupational orother important areas of functioning. These symptoms are not due to ageneral medical condition and are not better accounted for by anothermental disorder. Withdrawal usually, but not necessarily, is associatedwith substance dependence. Individuals with withdrawal have a craving toreadminister the substance to reduce these symptoms. Withdrawal developswhen doses of the substance are reduced or stopped.

Therefore, the term "cessation and withdrawal" shall include, but is notlimited to, the following conditions characterized in the DSM-IV:Nicotine Withdrawal; Nicotine-Related Disorder Not otherwise Specified;Nicotine Dependence, with physiological dependence; Nicotine Dependence,without physiological dependence; Nicotine Dependence, Early FullRemission; Nicotine Dependence, Early Partial Remission; NicotineDependence, Sustained Full Remission; Nicotine Dependence, SustainedPartial Remission; Nicotine Dependence, On Agonist Therapy; OpioidWithdrawal; Opioid-Related Disorder Not Otherwise Specified; OpioidDependence, with physiological dependence; Opioid Dependence, withoutphysiological dependence; Opioid Dependence, Early Full Remission;Opioid Dependence, Early Partial Remission; Opioid Dependence, SustainedFull Remission; Opioid Dependence, Sustained Partial Remission; OpioidDependence On Agonist Therapy; and Opioid Dependence in a controlledenvironment; Ethanol Withdrawal; Ethanol Dependence with PhysiologicalDependence; Ethanol Withdrawal, without Physiological Dependence;Ethanol Withdrawal, Early Full Remission; Ethanol Withdrawal, EarlyPartial Remission; Ethanol Withdrawal, Sustained Full Remission; EthanolWithdrawal, Sustained Partial Remission; Ethanol Withdrawal, on AgonistTherapy; and Ethanol Withdrawal, In a Controlled Environment.

The discontinued use of tobacco products, all of which contain nicotine,results in the onset of nicotine withdrawal conditions. Individualstypically suffer the symptoms of nicotine withdrawal as a consequence ofthe discontinued use of tobacco in any form, including, but not limitedto smoking of cigarette, cigar, or pipe tobacco, or the oral orintranasal ingestion of tobacco or chewing tobacco. Such oral orintranasal tobacco includes, but is not limited to snuff and chewingtobacco. The cessation of nicotine use or reduction in the amount ofnicotine use, is often followed within 24 hours by symptoms includingdysphoric, depressed mood; light-headedness; insomnia; irritability,frustration or anger; anxiety; nervous tremor; difficulty concentrating;restlessness; decreased heart rate; increased appetite or weight gain;and the craving for tobacco or nicotine. These symptoms often causeclinically significant distress or impairment in social, occupational,or other important areas of functioning. The present invention is mostpreferably used to alleviate one or more symptoms attributed to nicotinewithdrawal when such symptoms are not due to a general medical conditionand are not better accounted for by another medical disorder.

The present method is also helpful to those who have replaced, orpartially replaced, their use of tobacco with the use of nicotinereplacement therapy. Thus, such patients can be assisted to reduce andeven eliminate entirely their dependence on nicotine in all forms.

The discontinued or reduction in administration of an opioid, typicallyself-administration, through injection or orally, through smoking orintranasal ingestion, results in the presence of a characteristic opioidwithdrawal condition. This withdrawal condition is also precipitated byadministration of an opioid antagonist such as naloxone or naltrexoneafter opioid use. Opioid withdrawal is characterized by symptoms thatare generally opposite to the opioid agonist effects. These withdrawalsymptoms include anxiety; restlessness; muscle aches, often in the backand legs; craving for opioids; irritability and increased sensitivity topain; dysphoric mood; nausea or vomiting; lacrimation; rhinorrhoea;papillary dilation; piloerection; sweating; diarrhea; yawning; fever;and insomnia. When dependence is on short-acting opioids, such asheroin, withdrawal symptoms occur within 6-24 hours after the last dose,while with longer-acting opioids, such as methadone, symptoms may take2-4 days to emerge. These symptoms often cause clinically significantdistress or impairment in social, occupational or other important areasof functioning. The present invention is most preferably used toalleviate one or more symptoms attributed to opioid withdrawal when suchsymptoms are not due to a general medical condition and are not betteraccounted for by another medical disorder.

The discontinued or reduction in use of ethanol (ethanol containingbeverages) results in the onset of ethanol withdrawal conditions.Ethanol withdrawal conditions are characterized by symptoms that beginwhen blood concentrations of ethanol decline sharply, within 4 to 12hours after ethanol use has been stopped or reduced. These ethanolwithdrawal symptoms include craving for ethanol; autonomic hyperactivity(such as sweating or pulse rate greater than 100); hand tremor;insomnia; nausea; vomiting; transient visual, tactile, or auditoryhallucinations or illusions; psychomotor agitation; anxiety; and grandmal seizures. These symptoms often cause clinically significant distressor impairment in social, occupational, or other important areas offunctioning. The present invention is most preferably used to alleviateone or more symptoms attributed to ethanol withdrawal when such symptomsare not due to a general medical condition and are not better accountedfor by another medical disorder.

The method of the present invention is preferably administered inconnection with and/or subsequent to an educational and/or behavioralmodification program to enhance continued abstinence from tobacco,opioids, ethanol, or combinations thereof. The method of the presentinvention is also highly beneficial to such programs by alleviating thesuffering experienced from the nicotine, opioid, and ethanol withdrawalover the course of such programs. Therefore, the programs can be moreeffective by focusing on educational and behavioral modification goals,further reducing the incidence of program non-completion.

The compound4-chloro-5-(imidazoline-2-ylamino)-6-methoxy-2-methylpyrimidine isprepared generally as disclosed in U.S. Pat. No. 4,323,570. Preferably,4-chloro-5-(imidazoline-2-ylamino)-6-methoxy-2-methylpyrimidine isprepared as follows. ##STR1##

N-acetelimidazoline-2-one is prepared by reacting acetic anhydride with2-imidazolidone at room temperature. The reaction mixture is heated tobetween 80° C. and 100° C. for 90 minutes and then cooled to from about10° C. to about -10° C. to afford N-acetelimidazoline-2-one.

The first intermediate, 4,6-dihydroxy-2-10 methylpyrimidinamine, issynthesized by preparing sodium ethoxide in situ from sodium and anhydrous ethanol under a nitrogen blanket. Acetamidine hydrochloride anddiethyl malonate are added and the reaction mixture heated to boilingfor 2 to 5 hours to afford 4,6-dihydroxy-2-methylpyrimidine.

The second intermediate, 4,6-dihydroxy-2-methyl-5-nitropyrimidine, isthen synthesized by slowly adding 4,6-dihydroxy-2-methylpyrimidine to areaction mixture of fuming nitric acid in acetic acid. Once addition of4, 6-dihydroxy-2-methylpyrimidine is complete, the reaction mixture isstirred for one-half to 2 hours to afford4,6-dihydroxy-2-methyl-5-nitropyrimidine.

Following the nitration, phosphorous oxychloride (POCl₃) and4,6-dihydroxy-2-methyl-5-nitropyrimidine are combined with stirring. Tothis mixture, diethylaniline is added dropwise at a rate so that thereaction mixture temperature is maintained below about 40° C. After theaddition is complete, the reaction mixture is refluxed for one to threehours and then distilled under a vacuum to afford the thirdintermediate, 4,6-dichloro-2-methyl-5-nitropyrimidine.

The third intermediate, 4,6-dichloro-2-methyl-5-nitropyrimidine ishydrogenated over Raney-Ni as a 10% to 30% solution in toluene to affordthe corresponding compound, 4,6-dichloro-2-methyl-5-aminopyrimidine, asa fourth intermediate.

The fifth intermediate,N-(1-acetylimidazolin-2-ylidene)-4,6-dichloro-5-pyrimidinamine, is thenprepared by combining phosphorous oxychloride, N-acetylimidazolin-2-oneand 5-amino-4,6-dichloro-2-methylpyrimidine, and heating to boilingduring from 2 to 4 hours, and then cooling, with stirring to roomtemperature.

The final product,4-chloro-N-(imidazolin-2-ylidene)-6-methoxy-2-methyl-5-pyrimidinamine issynthesized by first preparing sodium methoxide in situ from anhydrousmethanol and sodium. The fifth intermediate,N-(1-acetylimidazolin-2-ylidene)-4,6-dichloro-2-methyl-5-pyrimidinamine,is added and the reaction mixture brought to a boil. From 15 minutes to1 hour after the reaction mixture is brought to a boil, further sodiummethoxide is added and the reaction mixture is maintained at a boil forfrom 15 minutes to 1 hour to afford4-chloro-N-(imidazolin-2-ylidene)-6-methoxy-2-methyl-5-pyrimidinamine.

Work-up of the several intermediates are carried out by standardtechniques well-known to those skilled in the art. The various reactantsand reagents used in this synthesis are commercially available orreadily prepared from commercially available material by standardmethods well-known to those skilled in the art.

It will be appreciated that the compound of the present invention may beisolated per se or may be converted to an acid addition salt usingconventional methods.

By the term "effective dose" is meant an amount of4-chloro-5-(imidazoline-2-ylamino)-6-methoxy-2-methylpyrimidine, or apharmaceutically acceptable salt thereof, which will diminish or relieveone or more symptoms or conditions resulting from cessation orwithdrawal of tobacco, nicotine, opioids, ethanol and combinationsthereof.

The compound of the present invention is an I₁ -imidazoline liganddemonstrating substantial selectivity for I₁ receptors over α₂adrenergic receptors. In saturation binding experiments in bovinerostral ventrolateral medulla (bovine RVLM), moxonidine demonstrates aselectivity value (K_(i) at α₂ sites in uM/K_(i) at I₁ sites in uM) ofgreater than 20 and preferably greater than 30 X, where K_(i) is theinhibitory affinity constant. Of course, K_(i) is inversely proportionalto affinity, so lower K_(i) values indicate higher affinity. Thus, thehigher the selectivity value, the more selective the compound. Incontrast, clonidine's selectivity value in bovine RVLM is less than 4.See Ernsberger et al., J. Pharmacol. Exp. Ther., 264, 172-182 (1993) fordetails on experimental protocol and results.

The dose of compound to be administered, in general, is from about 0.001to about 10.0 mg/day; as usual, the daily dose may be administered in asingle bolus, or in divided doses, depending on the judgment of thephysician in charge of the case. A more preferred range of doses is fromabout 0.002 to about 5.0 mg/day; other dosage ranges which may bepreferred in certain circumstances are from about 0.005 to about 2.0mg/day; from about 0.1 to about 1.0 mg/day; from about 0.05 to about 0.8mg/day; and a particularly preferred range is from about 0.05 to about0.6 mg/day. It will be understood that the dose for a given patient isalways to be set by the judgment of the attending physician, and thatthe dose is subject to modification based on the size of the patient,the lean or fat nature of the patient, the characteristics of theparticular compound chosen, the intensity of the patient's tobacco,opioid, ethanol or combinations thereof habit, the intensity of thepatient's withdrawal symptoms, and psychological factors which mayaffect the patient's physiological responses.

THE FORMULATIONS

Pharmaceuticals are substantially always formulated into pharmaceuticaldosage forms, in order to provide an easily controllable dosage of thedrug, and to give the patient an elegant and easily handled product. Thepresent compound is susceptible to formulation into the conventionalpharmaceutical dosage forms, including capsules, tablets, inhalants,injectable parenteral solutions and suppositories.

Usually the oral dosage forms, particularly tablets and capsules, aremost convenient for the patient and are usually preferred. Liquidsuspensions of pharmaceuticals, formerly popular, have now become lesspopular and are seldom used but the present compounds are entirelyamenable to such products should they be desired.

While it is possible to administer4-chloro-5-(imidazoline-2-ylamino)-6-methoxy-2-methylpyrimidinedirectly, it is preferably employed in the form of a pharmaceuticalformulation comprising a pharmaceutically acceptable carrier, diluent orexcipient and the compound. Such formulations will contain from about0.01 percent to about 99 percent of the compound.

In making the formulations of the present invention, the activeingredient will usually be mixed with at least one carrier, or dilutedby at least one carrier, or enclosed within a carrier which may be inthe form of a capsule, sachet, paper or other container usingconventional techniques and procedures for the preparing ofpharmaceutical formulations. When the carrier serves as a diluent, itmay be a solid, semi-solid or liquid material which acts as a vehicle,excipient or medium for the active ingredient. Thus, the formulationscan be in the form of tablets, granules, pills, powders, lozenges,sachets, cachets, elixirs, emulsions, solutions, syrups, suspensions,aerosols (as a solid or in a liquid medium) and soft and hard gelatincapsules.

Examples of suitable carriers, diluents and excipients include lactose,dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calciumphosphate, alginates, liquid paraffin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, tragcanth,gelatin, syrup, methylcellulose, methyl- and propylhydroxybenzoates,vegetable oils, such as olive oil, injectable organic esters such asethyl oleate, talc, magnesium stearate, water and mineral oil. Theformulations may also include wetting agents, lubricating, emulsifyingand suspending agents, preserving agents, sweetening agents, perfumingagents, stabilizing agents or flavoring agents. The formulations of theinvention may be formulated so as to provide immediate or nonimmediaterelease of the active ingredient, by procedures well-known in the art.Preferably, the formulations of the present invention will be formulatedto provide nonimmediate release of the active ingredient for oral ortransdermal administration.

In nonimmediate release dosage forms, release of the drug from itsdosage form is the rate limiting step in therelease-absorption-elimination kinetic scheme. This is distinguishedfrom the immediate release dosage forms where absorption of drug acrossa biological membrane is a rate limiting step. Nonimmediate releasedelivery systems have been divided into four categories: (1) delayedrelease; (2) sustained release; (3) site-specific release; and (4)receptor release.

Generally, delayed release systems are those that employ repetitive,intermediate dosing of a drug from one or more immediate release unitsincorporated into a single dosage form. Examples of delayed releasesystems include repeat action tablets and capsules and enteric-coatedtablets where timed release is achieved by a barrier coating.

Sustained release delivery systems include both controlled release andprolonged release. Generally, sustained release systems include any drugdelivery system that achieves slow release of drug over an extendedperiod of time. When the system maintains constant drug levels in theblood or target tissue. It is considered a controlled release system.Where the system extends the duration of action over that afforded by aconventional delivery system, it is considered a prolonged releasesystem.

Site-specific and receptor release systems refer to targeting of a drugdirectly to a desired biological location. In the case of site-specificrelease, a target is a particular organ or tissue. Analogously, in thecase of receptor release, the target is the particular receptor for adrug within a particular organ or tissue.

Typical oral nonimmediate release forms include diffusional systems anddissolution systems. In diffusional systems, the release rate of drug isdetermined by its diffusion through a water-insoluble polymer. There aregenerally two types of diffusional devices, reservoir devices in which acore of drug is surrounded by polymeric membrane; and matrix devices inwhich dissolved or dispersed drug is distributed substantially uniformlyand throughout an inert polymeric matrix. In actual practice, manysystems that utilize diffusion may also rely to some extent ondissolution to determine the release rate.

Common practices utilized in developing reservoir systems includemicroencapsulation of drug particles and press-coating of whole tabletsor particles. Frequently, particles coated by microencapsulation form asystem where the drug is contained in the coating film as well as in thecore of the microcapsule. Drug release typically includes a combinationof dissolution and diffusion with dissolution being the process thatcontrols the release rate. Common material is used as the membranebarrier coat, alone or in combination, are hardened gelatine, methyl andethylcellulose, polyhydroxymethacrylate, hydroxypropylcellulose,polyvinylacetate, and various waxes.

In matrix systems, three major types of materials are frequently used inthe preparation of the matrix systems which include insoluble plastics,hydrophilic polymers, and fatty compounds. Plastic matrices which havebeen employed include methyl acrylate-methyl methacrylate, polyvinylchloride and polyethylene. Hydrophilic polymers include methylcellulose, hydroxypropylcellulose and sodiumcarboxymethylcellulose.Fatty compounds include various waxes such as carnauba wax, and glyceryltristearate. Preparation of these matrix systems are by methods wellknown to those skilled in the art. These methods of preparationgenerally comprise mixing the drug with the matrix material andcompressing the mixture into tablets. With wax matrixes, the drug isgenerally dispersed in molten wax, which is then congealed, granulatedand compressed into cores. As with other nonimmediate systems, it iscommon for a portion of the drug to be available immediately as apriming dose and the remainder to be released in a sustained fashion.This is generally accomplished in the matrix system by placing a primingdose in a coat on the tablet. The coat can be applied by press coatingor by conventional pan or air suspension coating.

Dissolution systems generally are products that have a decreaseddissolution rate where the drug is highly soluble. Several approaches toachieving a slow dissolution rate include preparing an appropriate saltor derivative of the active agent, by coating the drug with a slowlydissolving material, or by incorporating the drug into a tablet with aslowly dissolving carrier. Encapsulated dissolution systems are preparedeither by coating particles or granules of drug with varying thickness'of slowly soluble polymers or by microencapsulation. The most commonmethod of microencapsulation is coacervation, which involves addition ofa hydrophilic substance to a coloidal dispersion. The hydrophilicsubstance, which operates as the coating material, is selected from awide variety of natural and synthetic polymers including shellacs,waxes, starches, cellulose acetate, phthalate or butyrate,polyvinylpyrrolidone, and polyvinyl chloride. After the coating materialdissolves, the drug inside the microencapsule is immediately availablefor dissolution and absorption. Drug release, therefore, can becontrolled by adjusting the thickness and dissolution rate of the coat.For example, the thickness can be varied from less than one μm to 200 μmby changing the amount of coating material from about 3 to about 30percent by weight of the total weight. By employing differentthickness', typically three of four, the active agent will be releasedat different, predetermined times to afford a delayed release affect.Coated particles can, of course, be directly compressed into tablets orplaced into capsules.

Matrix dissolution systems are prepared by compressing the drug with aslowly dissolving polymer carrier into a tablet. Generally there are twomethods for preparing drug-polymer particles, congealing and aqueousdispersion methods. In the congealing method, the drug is mixed with apolymer or wax material and either cooled or cooled and screened orspray-congealed. In the aqueous dispersion method, the drug-polymermixture is simply sprayed or placed in water and the resulting particlesare collected.

Osmotic systems are also available where osmotic pressure is employed asthe driving force to afford release of a drug. Such systems generallyconsist of a core of drug surrounded by a semipermeable membranecontaining one or more orifices. The membrane allows diffusion of waterinto the core, but does not allow release of the drug except through theorifices. Examples of materials used as the semipermeable membraneinclude polyvinyl alcohol, polyurethane, cellulose acetate,ethylcellulose, and polyvinyl chloride.

A further system comprises ion-exchange resins. These resins arewater-insoluble cross-linked polymers containing salt forming groups inrepeating positions on the polymer chain. The active agent is bound tothe resin by repeated exposure of the resin to the drug in achromatographic column, or by prolonged contact of the resin with asolution of the drug. Drug release from the drug-resin complex dependson the ionic environment; that is pH and electrolyte concentrationwithin the gastrointestinal tract, as well as the specific properties ofthe resin. Drug molecules attached to the resin are released by changingwith appropriately charged ions in the gastrointestinal tract followedby infusion of the free drug molecule out of the resin. Generally, therate of diffusion is controlled by the area of diffusion, diffusionalpath link, and extent of crosslinking in the resin. A furthermodification of the release rate can be afforded by coating thedrug-resin complex.

The most common types of dosage forms used for parenteral nonimmediaterelease drug therapy are intramuscular injections, implants forsubcutaneous tissues and various body cavities, and transdermal devices.Generally, intramuscular injections involve a formation of a dissociablecomplex of a drug with another molecule. In this sense, thedrug-molecule complex serves as a reservoir at the site of injection fordrug release to the surrounding tissues. Examples of macromoleculesinclude biological polymers such as antibodies and proteins or syntheticpolymers such as polyvinylpyrrolidone, and polyethylene glycol.

Complexes can also be formed between drugs and small molecules. When thedrug molecule is large relative to the complexing agent, the associationconstant will be greater and the complex more stable. Examples forsmaller molecules include zinc, optionally suspended in a gelatinsolution or an oil solution. An alternative dosage form for anintramuscular injection is an aqueous suspension. By varying viscosityand particle size a stable suspension of active ingredient can beafforded. Another common approach to decreased dissolution rate is todecease the saturation solubility of the drug. This is accomplishedthrough the formation of less soluble salts and prodrug derivatives andby employing polymorphic crystal forms of the active ingredient.

Another approach is a use of oil solutions and oil suspensions. As willbe appreciated by those skilled in the art, those drugs havingappreciable oil solubility and the desired partition characteristics aremost suitable for this approach. Examples of oils which may be used forintramuscular injection include sesame, olive, arachnis, maize, almond,cotton seed and caster oil. With oil suspensions, drug particles mustfirst dissolve in the oil phase and then partition into the aqueousmedium.

Emulsions comprising oil-in-water emulsions or water-in-oil emulsionsmay also be used.

Implants comprise a drug-barring polymeric device which is insertedsubcutaneously or in various body cavities. The polymer material whichis used must, of course, be biocompatible and nontoxic and are typicallychosen from among hydrogels, silicones, polyethylenes, ethylene-vinylacetate copolymers, and biodegradable polymers. Hydrogels generally area polymeric material that exhibit the ability to swell in water andretain greater than 20 percent of that water within its structure, butwhich will not dissolve in water. Small molecular weight substances arecapable of diffusing through hydrogels. Specific example of hydrogelsinclude polyhydroxyalkyl methacrylates, polyacrylamide andpolymethacrylamide, polyvinylpyrrolidone, polyvinyl alcohol, and variouspolyelectrolyte complexes.

Additional systems include subcutaneous devices, and intravaginaldevices.

Percutaneous drug absorption, more commonly referred to as transdermalsystems, generally includes the use of microporous membranes as the ratecontrolling barrier. Microporous membranes are films varying inthickness with pore sizes ranging from several micrometers to a fewangstroms. Examples of material from which such membranes are madeinclude regenerated cellulose, cellulose nitrates/acetate, cellulosetriacetate, polypropylene, polycarbonate and polytetrafluoroethylene.The barrier properties of these various films depend upon the method ofpreparation, the medium with which the pores are filled, pore diameter,percent porosity, and tortuosity.

An example of a transdermal system is disclosed in U.S. Pat. No.4,201,211.

Targeted delivery systems include nanoparticles and liposomes.Nanoparticles are examples of systems known collectively as colloidaldrug delivery systems. Other members in this group includemicrocapsules, nanocapsules, macromolecular complexes, polymeric beads,microspheres and liposomes. Generally, a nanoparticle is a particlecontaining dispersed drug with a diameter of 200-500 nm. Materials usedin the preparation of nanoparticles are sterilisable, nontoxic andbiodegradable. Examples include albumen, ethylcellulose, casein andgelatin. Typically, they are prepared by procedures similar to thecoacervation method of microencapsulation.

Liposomes, generally, are phospholipids that when dispersed with aqueousmedia swell, hydrate and form multilamellar concentric bilayer vesicleswith layers of aqueous media separating the lipid bilayers.Phospholipids can also form a variety of structures other than liposomeswhen dispersed in water depending on the molar ration of lipid to water.At low ratios, the liposome is the preferred structure. The actualphysical characteristics of the liposomes depend on pH, ionic strengthand the presence of divalent cations. They show low permeability toionic and polar substances but at elevated temperatures undergo a phasetransition which alters their permeability. Polar drugs are trapped inthe aqueous spaces and nonpolar drugs bind to the lipid bilayer ofvesicle. Polar drugs are released when the bilayer is broken or bypermeation, but nonpolar drugs remain affiliated with the bilayer untilit is disrupted by temperature or exposure to lipoproteins. Theliposome, of course, acts as the carrier or the active agent.

Depending on the method of administration, the formulations for thetreatment of the nicotine withdrawal, opioid withdrawal, ethanolwithdrawal and combinations thereof, conditions may be formulated astablets, capsules, injection solutions for parenteral use, gel orsuspension for transdermal delivery, suspensions or elixirs for oral useor suppositories. Preferably the compositions are formulated in a unitdosage form, each dosage containing from 0.01 to 0.4 mg, more usually0.05 to 0.3 mg, of the active ingredient. The term "unit dosage form"refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, related to the desired daily or divided dose, inassociation with a suitable pharmaceutical carrier, diluent or excipienttherefor. When a sustained release formulation is desired, the unitdosage form may contain from 0.01 to 2.0 mg of the active ingredient. Apreferred formulation of the invention is a nonimmediate release ortransdermal patch comprising 0.01 to 2.0 mg or 0.05 to 2.0 mg of activeingredient together with a pharmaceutically acceptable carrier therefor.

In order to more fully illustrate the operation of this invention, thefollowing examples of formulations are provided. The examples areillustrative only and are not intended to limit the scope of theinvention.

FORMULATION 1

Hard gelatin capsules are prepared using the following ingredients:

    ______________________________________                                                       Amt. per                                                                             Concentration by                                                       Capsule                                                                              Weight (percent)                                        ______________________________________                                        4-chloro-5-(imidazoline-2-                                                                      10 mg    4.2                                                ylamino)-6-methoxy-2-                                                         methylpyrimidine                                                              Starch dried     220 mg   91.7                                                Magnesium stearate                                                                              10 mg    4.2                                                                 240 mg   101.1                                               ______________________________________                                    

The above ingredients are mixed and filled into hard gelatin capsules in240 mg quantities.

FORMULATION 2

Capsules each containing 10 mg of medicament are made as follows:

    ______________________________________                                                       Amt. per                                                                             Concentration by                                                       Capsule                                                                              Weight (percent)                                        ______________________________________                                        4-chloro-5-(imidazoline-2-                                                                     10 mg     5.3                                                ylamino)-6-methoxy-2-                                                         methylpyrimidine                                                              Starch dried     89 mg    46.8                                                Microcrystalline cellulose                                                                     89 mg    46.8                                                Magnesium stearate                                                                              2 mg     1.1                                                                 190 mg   100.0                                               ______________________________________                                    

The active ingredient, cellulose, starch and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve and filled into a hardgelatin capsule.

FORMULATION 3

Capsules each containing 10 mg of active ingredient are made as follows:

    ______________________________________                                                       Amt. per                                                                             Concentration by                                                       Capsule                                                                              Weight (percent)                                        ______________________________________                                        4-chloro-5-(imidazoline-2-                                                                      10 mg    3.2                                                ylamino)-6-methoxy-2-                                                         methylpyrimidine                                                              Polyoxyethylenesorbitan                                                                         50 mg   16.1                                                monooleate                                                                    Magnesium stearate                                                                             250 mg   80.6                                                                 310 mg   99.9                                                ______________________________________                                    

The above ingredients are thoroughly mixed and placed in an emptygelatin capsule.

FORMULATION 4

Tablets each containing 10 mg of active ingredient are made up asfollows:

    ______________________________________                                                       Amt. per                                                                             Concentration by                                                       Capsule                                                                              Weight (percent)                                        ______________________________________                                        4-chloro-5-(imidazoline-2-                                                                     10 mg    10.0                                                ylamino)-6-methoxy-2-                                                         methylpyrimidine                                                              Starch           45 mg    45.0                                                Microcrystalline cellulose                                                                     35 mg    35.0                                                Polyvinyl (pyrrolidone (as 10%                                                                  4 mg     4.0                                                solution in water)                                                            Sodium carboxyethyl starch                                                                     4.5 mg    4.5                                                Magnesium stearate                                                                             0.5 mg    0.5                                                Talc              1 mg     1.0                                                                 100 mg   100.0                                               ______________________________________                                    

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granule so produced isdried at 50°-60° C. and passed through No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate and talc, previouslypassed though a No. 60 mesh U.S. sieve, are then added to the granulewhich, after mixing, is compressed on a tablet machine to yield a tabletweighing 100 mg.

FORMULATION 5

A tablet formula may be prepared using the ingredients below:

    ______________________________________                                                       Amt. per                                                                             Concentration by                                                       Capsule                                                                              Weight (percent)                                        ______________________________________                                        4-chloro-5-(imidazoline-2-                                                                      5 mg     1.2                                                ylamino)-6-methoxy-2-                                                         methylpyrimidine                                                              Cellulose microcrystalline                                                                     400 mg   95.2                                                Silicon dioxide fumed                                                                           10 mg    2.4                                                Stearic acid      5 mg     1.2                                                                 420 mg   100.0                                               ______________________________________                                    

The components are blended and compressed to form tablets each weighing420 mg.

FORMULATION 6

Suspensions each containing 5 mg of medicament per 40 ml dose are madeas follows:

    ______________________________________                                                       Per 5 ml of suspension                                         ______________________________________                                        4-chloro-5-(imidazoline-2-                                                                      5 mg                                                        ylamino)-6-methoxy-2-                                                         methylpyrimidine                                                              Sodium carboxymethyl                                                                           50 mg                                                        cellulose                                                                     Syrup            1.25 ml                                                      Benzoic acid solution                                                                          0.10 ml                                                      Flavor           q.v.                                                         Color            q.v.                                                         Water            q.s. to 5 ml                                                 ______________________________________                                    

The medicament is passed through a No. 45 mesh U.S. sieve and mixed withthe sodium carboxymethylcellulose and syrup to form a smooth paste. Thebenzoic acid solution, flavor and color is diluted with some of thewater and added, with stirring. Sufficient water is then added toproduce the required volume.

THE TESTING METHODS

The usefulness of the compound for treating a condition resulting fromcessation and withdrawal from the use of nicotine and lack of sedatingeffect was supported by the following studies.

I. Auditory Startle Response.

Animals:

Male Long Evans rats (Harlan Sprague Dawley, Columbus, Ind.) areindividually housed in a controlled environment on a 12 hour light-darkcycle. The rats are given free access to food (Purina Rodent Chow) andwater. All treatment groups contain from 8 to 10 rats.

Chronic Nicotine Treatment:

The rats are anesthetized with isoflurane and Alzet osmotic minipumps(Alza Corporation, Palo Alto, Calif. Model 2ML2) are implantedsubcutaneously. Nicotine ditartrate is dissolved in physiologicalsaline. Pumps are filled with nicotine ditartrate (6 mg/kg base/day) orphysiological saline. Twelve days following implantation of pumps, ratsare anesthetized with isoflurane and the pumps are removed.

Auditory Startle Response Observation:

The sensory motor reactions auditory startle response (peak amplitude,V_(max))! of individual rats are recorded using San Diego Instrumentsstartle chambers (San Diego, Calif.). Startle sessions consist of a 5minute adaptation period at background noise level of 70 +/-2 dBAimmediately followed by 25 presentations of auditory stimuli (120 +/-2dBA noise, 50 ms duration) presented at 8 second intervals. Peak startleamplitudes are averaged for all 25 presentations of stimuli for eachsession. Auditory startle responding is evaluated daily at 24 hourintervals on days 1, 2, and 3 following nicotine withdrawal.

The 4-chloro-5-(imidazoline-2-ylamino)-6-methoxy-2-methylpyrimidinecompound is administered subcutaneously at three doses about 15 minutesbefore startle testing each day. Clonidine was also tested.

Ambulatory Activity Evaluation

Spontaneous activity of male Long Evans rats was recorded usingMulti-Varimax Activity Monitors (Columbus Instruments, Columbus, Ohio).Interruptions of three individual infrared photocells were recorded bycomputer. Activity counts were accumulated at 15 minute intervals for 1hour immediately following administration of4-chloro-5-(imidazoline-2-ylamino)-6-methoxy-2-methylpyrimidine (0.01,0.1, 1 mg/kg, s.c.), clonidine (0.1, 0.3, 1.0 mg/kg, s.c.), or thesaline control. Ambulatory activity counts represent the sum ofindividual photocell beam breaks within a representative time interval.

Results:

As illustrated in Tables 1, 2, 3 and 4 subcutaneous administration of4-chloro-5-(imidazoline-2-ylamino)-6-methoxy-2-methylpyrimidine(Moxonidine) 15 minutes prior to startle testing significantlyattenuated the effects of nicotine withdrawal of the auditory startlereflex.

The compounds were as follows:

A. Moxonidine

B. Clonidine

                  TABLE 1                                                         ______________________________________                                        Chronic          Startle Response (μV)                                     Treatment Pre-Treatment                                                                            Day 1     Day 2 Day 3                                    ______________________________________                                        Saline    Saline     229*      258*  248*                                     Nicotine  Saline     368       356   382                                      Nicotine  Compound A 406       379   277                                                0.00003 mg/kg                                                       Nicotine  Compound A 271*      269*  278*                                               0.0001 mg/kg                                                        Nicotine  Compound A 237*      247*  220*                                               0.0003 mg/kg                                                        Nicotine  Compound B 189*      233*  209*                                               0.001 mg/kg                                                         ______________________________________                                         *Significantly different from Nicotine/Saline control, P < 0.05          

                  TABLE 2                                                         ______________________________________                                        Chronic            Startle Response (μV)                                   Treatment  Pre-Treatment                                                                             Day 1    Day 2                                         ______________________________________                                        Saline     Saline      201      236                                           Nicotine   Saline      298*     302*                                          Nicotine   Compound B  288*     325*                                                     0.0001 mg/kg                                                       Nicotine   Compound B  231      317*                                                     0.0003 mg/kg                                                       Nicotine   Compound B  196      256                                                      0.001 mg/kg                                                        ______________________________________                                         *Significantly different from Saline/Saline control, P < 0.05            

                  TABLE 3                                                         ______________________________________                                        Acute Effect                                                                  Pre-Treatment    Startle Response (μV)                                     ______________________________________                                        Saline           211                                                          Compound A 0.001 mg/kg                                                                         230                                                          Compound A 0.01 mg/kg                                                                          213                                                          Compound A 0.1 mg/kg                                                                           203                                                          Compound A 1.0 mg/kg                                                                            105*                                                        ______________________________________                                         *Significantly different from Saline control, P < 0.05                   

                  TABLE 4                                                         ______________________________________                                        Acute Effect                                                                                   Startle Response (μV)                                     Pre-Treatment    Day 1                                                        ______________________________________                                        Saline           182                                                          Compound B 0.003 mg/kg                                                                         168                                                          Compound B 0.01 mg/kg                                                                          148                                                          Compound B 0.03 mg/kg                                                                           135*                                                        Compound B 0.1 mg/kg                                                                            126*                                                        Compound B 0.3 mg/kg                                                                            50*                                                         ______________________________________                                         *Significantly different from Saline control, P < 0.05                   

                  TABLE 5                                                         ______________________________________                                        Spontaneous Activity Levels (Counts)                                                     Time (minutes)                                                     Treatment    15     30          45   60                                       ______________________________________                                        Vehicle      82     48          46   31                                       Compound A   95     52          44   36                                       0.01 mg/kg                                                                    Compound A   75     38          31   21                                       0.1 mg/kg                                                                     Compound A   65      19*         4*   7                                       1.0 mg/kg                                                                     Compound B    33*    16*         14* 15                                       0.03 mg/kg                                                                    ______________________________________                                         *Significantly different from Vehicle control, P < 0.05.                 

Conclusion

As can be seen in Table 2 above, subcutaneously administered clonidinedoes effectively reduce the elevation in startle reactivity typicallyobserved in rats experiencing nicotine withdrawal. The ED₅₀ forsubcutaneously administered clonidine in this model is approximately0.0004 mg/kg.

Treatment with moxonidine prior to startle testing during nicotinewithdrawal also effectively blocks the hyperreactivity that is typicallyseen (ED₅₀ approximately 0.00007 mg/kg; see Table 1, above). These dataindicate that moxonidine may be a useful as an aid to smoking cessationand nicotine withdrawal in mammals at a significant and unexpected lowerdoses than clonidine.

Since the effects observed on auditory startle might be partiallyproduced by drug related sedation or the inability to respond on thestartle task, rats were also evaluated to determine the comparativeeffects of moxonidine and clonidine on locomotor activity and startleresponding in non-nicotine dependent animals.

The results of activity testing for clonidine and moxonidine arepresented above in Table 5. As can be seen, clonidine significantlyreduced ambulatory activity at doses ≧0.03 mg/kg. Moxonidine alsoreduced ambulatory activity but a dose of 1 mg/kg was required toproduce a reduction in ambulatory activity similar to the reduction seenwith a 0.03 mg/kg dose of clonidine.

Both compounds also reduce auditory startle responding (see Tables 3 and4) at doses that are equivalent to the doses which reduce ambulation.Again, clonidine is more potent than moxonidine in reducing baselinestartle responding.

These data indicate that clonidine produces sedation and interferes withresponding at more than 30-fold lower doses than moxonidine.

                  TABLE 6                                                         ______________________________________                                        Comparison of Moxonidine and Clonidine                                                          Moxonidine                                                                              Clonidine                                         Assay             (mg/kg)   (mg/kg)                                           ______________________________________                                        Nicotine Withdrawal (ED50)                                                                        0.00007  0.0004                                           Baseline Startle (MED)                                                                          1.0       0.03                                              Locomotor activity (MED)                                                                        1.0       0.03                                              ______________________________________                                    

Clonidine is able to reduce the nicotine withdrawal-enhanced acousticstartle reflex. However, clonidine also produces sedating side effectsat doses that are less than 100-fold higher than the ED₅₀ in thenicotine withdrawal assay. This poor separation between efficacy andside effects for clonidine in the rat is expected to parallel its narrowtherapeutic window in the treatment of smoking cessation and nicotinewithdrawal in man. Moxonidine is more potent than clonidine in thenicotine withdrawal assay and produces sedating side effects only atdoses that are greater than 10,000-fold higher than the ED₅₀ in thenicotine withdrawal assay. Therefore, moxonidine will have good efficacyas an aid to smoking cessation and nicotine withdrawal without producingthe side effects observed with clonidine.

The usefulness of the compound for treating a condition resulting fromcessation and withdrawal from opioid use was supported by the followingstudies.

Materials

Opioid Dependence and Withdrawal

Opioid dependence was induced in male Sprague-Dawley rats (CharlesRiver, 250-350 g) by the s.c. implantation of morphine pellets. Underhalothane anesthesia animals were implanted with two pellets (75 mg ofmorphine/pellet) daily for two days. Withdrawal was induced 48 hoursafter the last set of pellets was implanted; all four pellets wereremoved one hour before precipitating withdrawal. Withdrawal was inducedby administering the opioid antagonist naltrexone HCl (10 mg/kg; Sigma)s.c.

Behavioral Ratings

For the behavioral assessment of opioid withdrawal animals were studiedin clear plexiglass cages (18×10×8 inches) and remained in these cagesfor the entire study. Animals were adapted to the cages for 15 minutesand were then administered a pretreatment of either moxonidine or saline(1 ml/kg s.c.). Naltrexone was administered 15 minutes after thepretreatment. Eleven previously identified behaviors characteristic ofthe rat opioid abstinence syndrome were assessed (see Himmelsback et al,1935; Way et al., 1969; Wei, 1973; Blasig et al., 1973; Aceto et al.,1986). The absolute frequency of seven episodic behaviors was recordedand a score was calculated based on multiples of five incidents (0=noincidents; 1=1-5 incidents, etc.). Behaviors scored in this mannerincluded: teeth chatter (separated by at least 3s), jumping, wet-dogshakes, writhing, diarrhea, digging and erections. Chewing (without anymatter in the mouth) was similarly scored in multiples of 100occurrences. Three withdrawal behaviors could not be defined in discreteepisodes and the severity of these behaviors was assessed duringpredefined anchor points on a four point scale: 0=absent; 1=mild;2=moderate; 3=marked. Behaviors rated in this fashion were lacrimation,ptosis, and salivation. The amount of weight loss was measured at theend of the rating period (i.e. 1 hour after the administration ofnaltrexone) and a score was calculated based on multiples of 5 g (0=noloss; 1=1-5 g; 2=6-10 g; 3=11-15 g, etc.)

                  TABLE 7                                                         ______________________________________                                                  Pretreatment                                                        Time post              Moxonidine                                                                              Moxonidine                                   Naltrexone (min)                                                                          Saline     1 mg/kg   10 mg/kg                                     ______________________________________                                        -15 to 0    1.5        2         1.5                                           0 to 15    15.25      12.5      11.5                                         15 to 30    17.125     12        10.5*                                        30 to 45    18.125     13         7.5*                                        45 to 60    16.25      11         3*                                          ______________________________________                                         *Significantly different from saline control, P < 0.05.                  

We claim:
 1. A method for treating a condition resulting from thecessation or withdrawal of ethanol comprising administering to a mammalin need of such treatment, an effective amount of4-chloro-5-(imidazoline-2-ylamino)-6-methoxy-2-methylpyrimidine, or apharmaceutically acceptable salt thereof.
 2. A method of claim 1 whereinthe condition is selected from the group consisting of EthanolWithdrawal; Ethanol-Related Disorder Not otherwise Specified; EthanolDependence, with physiological dependence; Ethanol Dependence, withoutphysiological dependence; Ethanol Dependence, Early Full Remission;Ethanol Dependence, Early Partial Remission; Ethanol Dependence,Sustained Full Remission; Ethanol Dependence, Sustained PartialRemission; Ethanol Dependence, On Agonist Therapy; and EthanolDependence, in a Controlled Environment.
 3. A method of claim 2 whereinthe condition is Ethanol Withdrawal.
 4. A method of claim 1 wherein aneffective dose is from about 0.001 mg to about 10.0 mg per day.
 5. Amethod for inhibiting one or more symptoms from the cessation orwithdrawal of ethanol comprising administering to a mammal in need ofsuch treatment, an effective amount4-chloro-5-(imidazoline-2-ylamino)-6-methoxy-2-methylpyrimidine, or apharmaceutically acceptable salt thereof.
 6. A method of claim 5 whereinsaid symptom is selected from the group consisting of autonomichyperactivity; hand tremor; insomnia; nausea; vomiting; transientvisual; tactile or auditory hallucinations or illusions; psychomotoragitation; anxiety; seizures; and ethanol craving.
 7. A method of claim5 wherein an effective dose is from about 0.001 mg to about 10.0 mg perday.